**1. Introduction**

Modern vaccine development began from the use of vaccinia against smallpox by British physician Edward Jenner in the late eighteenth century and ever since has brought many products that have saved countless human lives from being claimed by numerous infectious pathogens, such as smallpox, measles, and rabies [1]. However, many pathogens such as human immunodeficiency virus (HIV), herpes simplex virus (HSV), and Ebola virus (EBV), still lack vaccines and are still posing a great threat to human health and life [2].

response to the Ag or changes the type of immune response with some mechanisms that are not exactly known but are argued relevant to two fundamental aspects: (1) giving off dangerous signals by imposing damages on cells/tissues to activate the innate immune cells; (2) exciting PRRs of the innate immune cells, such as DCs, MPs, histiocytes and mast cells, to sponsor the subsequent adaptive responses [11, 12]. The available adjuvants are mainly micron- or nanometer-sized particles or aggregates which may be classified into two types: (1) the natural or synthetic substances with intrinsic adjuvanticity, such as alum (insoluble aluminum salt), squalene/squalane, saponin, chitosan, hyaluronic acid (HA), and various pattern recognition receptor agonists (PRRas); (2) functional carriers capable of playing roles of both adjuvant and delivery, thus regarded as vaccine adjuvant delivery system (VADSs), which are often formulated with nanoparticles (NPs) fabricated with various biocompatible materials, such as liposomes made of phospholipids and cholesterol, immune stimulating complexes (ISCOMs) of saponin and lipids, polymeric NPs made of PLGA or polystyrene, virus-like particles (VLPs) made of viral proteins, emulsions made of squalene and surfactants, and the metal NPs (mNPs) made of aluminum or gold metal compounds, which prove

Vaccine Adjuvant Delivery Systems Constructed Using Biocompatible Nanoparticles Formed…

http://dx.doi.org/10.5772/intechopen.79905

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an efficient VADSs able to enormously enhance vaccination efficacy [3, 13].

**2. VADS constructed with different types of NPs formed by** 

**2.1. VADS constructed with metal nanoparticles (mNPs) formed by self-aggregation**

Alum is the micron-sized aggregates of water-insoluble aluminum salts and is the first substance that was discovered able to boost the efficacy of vaccines and coined the term "vaccine adjuvant," a concept which was put forward when scientists came to realize that certain materials irrelevant to pathogens but able to enhance immunoresponse induced by vaccine [14]. Since 1926, when first being used as an adjuvant, alum, such as aluminum phosphate, aluminum potassium sulfate, and aluminum hydroxide had been the only clinically used adjuvant in many subunit vaccines as well as the inactivated pathogen-based vaccines, until the approval of adjuvant calcium phosphate in diphtheria/pertussis (DT) vaccines [15]. Subsequently, an O/W nanoemulsions formed of squalene/Span 85/Tween 80, called MF59® was marketed as a VADS for delivering an influenza vaccine (Fluad®) in 1997, followed by AS04 (MPL/alum mixture) for delivering human papillomavirus (HPV, Cervarix®) and hepatitis B virus (HBV, Fendrix®) vaccines [16]. Alum forms a micron-sized VADS by just mixing the insoluble salt with other vaccine components or Ags and tends to function eliciting humoral over cellular immunity when

range of infectious pathogens.

**self-assembly of small molecules**

In this chapter, we describe design principles, main formulations and the state-of-the-art advances in developing novel VADSs constructed with different types of NPs, which are formed through small molecule self-assembly and herein, include liposomes, nondegradable inorganic metal NPs (mNPs), emulsions, ISCOMs. These small molecule-based NPs have been devised as a VADS with the potential to stimulate the Ag-specific humoral and cellular immune responses and are promising in preparation of next generation vaccines against a

Vaccines are developed based on the antigenic components, which can stimulate the host immune system to set up immunity able to clear the abnormalities and usually include three types: the live attenuated whole microbe vaccines, the killed whole microbe vaccines, and the antigenic component-based subunit vaccines [3]. The former two types are regarded as the conventional vaccines with a high capacity of defending against deleterious organisms but, unfortunately, are also linked to a relatively poor safety profile due to their possible reversion of virulence and induction of deviated immunoresponses leading to unprotective and even harmful immunity and unacceptable inflammation. In contrast, the subunit vaccine is elaborately formulated with defined components including antigen (Ags) to induce immunoresponses which is accurately targeting the matched objects, thus causing few safety concerns and can be employed to fight both infectious pathogens and detrimental neoplasms carrying the identical Ags. Subunit vaccines since the notion emergence have attracted great research interests with numerous visible and all imaginable advantages [4], including high safety without reversion to virulent state; their production needing no dangerous microorganisms; providing an alternative solution to the problematic culture for attenuating some pathogens; low risk of allergic or autoimmune reactions; customization to recognize certain pathogen-associated targets; feasible developing anticancer vaccine; carrying several peptide epitopes targeting different stages in the life cycle or subtypes of a pathogen; production in large scale in a pure state, in an economically and highly reproducible manner; high solubility allowing lyophilization to form stable dry products [4].

However, subunit vaccines often show a weak immune induction potency, due to lack of a large fraction of components associated with pathogen structural characteristics, which are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs) and able to activate the pattern recognition receptors (PRRs), such as the toll-like receptors (TLRs), the nucleotidebinding oligomerization domain-like receptors (NOD-like receptors), retinoic-acid-inducible gene-I-like receptors (RIG-I-like receptors), and C-type lectin receptors, to trigger as immunostimulators or an adjuvant mammalian innate immunoresponse sponsoring a series of adaptive reactions required for establishing the Ag-specific immunity [5]. Thus, while subunit vaccines are usually safer and less reactogenic than the whole organism vaccines, they often need an adjuvant or a vaccine adjuvant delivery system (VADS) to synergistically stimulate professional Ag-presenting cells (APCs) such as dendritic cells (DCs) and macrophages (MPs) for enhancing their immunization efficacy [6–10]. An adjuvant is a nonspecific immune-potentiating substance, which is capable of enhancing the body's immune response to the Ag or changes the type of immune response with some mechanisms that are not exactly known but are argued relevant to two fundamental aspects: (1) giving off dangerous signals by imposing damages on cells/tissues to activate the innate immune cells; (2) exciting PRRs of the innate immune cells, such as DCs, MPs, histiocytes and mast cells, to sponsor the subsequent adaptive responses [11, 12]. The available adjuvants are mainly micron- or nanometer-sized particles or aggregates which may be classified into two types: (1) the natural or synthetic substances with intrinsic adjuvanticity, such as alum (insoluble aluminum salt), squalene/squalane, saponin, chitosan, hyaluronic acid (HA), and various pattern recognition receptor agonists (PRRas); (2) functional carriers capable of playing roles of both adjuvant and delivery, thus regarded as vaccine adjuvant delivery system (VADSs), which are often formulated with nanoparticles (NPs) fabricated with various biocompatible materials, such as liposomes made of phospholipids and cholesterol, immune stimulating complexes (ISCOMs) of saponin and lipids, polymeric NPs made of PLGA or polystyrene, virus-like particles (VLPs) made of viral proteins, emulsions made of squalene and surfactants, and the metal NPs (mNPs) made of aluminum or gold metal compounds, which prove an efficient VADSs able to enormously enhance vaccination efficacy [3, 13].

**1. Introduction**

10 Immunization - Vaccine Adjuvant Delivery System and Strategies

Modern vaccine development began from the use of vaccinia against smallpox by British physician Edward Jenner in the late eighteenth century and ever since has brought many products that have saved countless human lives from being claimed by numerous infectious pathogens, such as smallpox, measles, and rabies [1]. However, many pathogens such as human immunodeficiency virus (HIV), herpes simplex virus (HSV), and Ebola virus (EBV),

Vaccines are developed based on the antigenic components, which can stimulate the host immune system to set up immunity able to clear the abnormalities and usually include three types: the live attenuated whole microbe vaccines, the killed whole microbe vaccines, and the antigenic component-based subunit vaccines [3]. The former two types are regarded as the conventional vaccines with a high capacity of defending against deleterious organisms but, unfortunately, are also linked to a relatively poor safety profile due to their possible reversion of virulence and induction of deviated immunoresponses leading to unprotective and even harmful immunity and unacceptable inflammation. In contrast, the subunit vaccine is elaborately formulated with defined components including antigen (Ags) to induce immunoresponses which is accurately targeting the matched objects, thus causing few safety concerns and can be employed to fight both infectious pathogens and detrimental neoplasms carrying the identical Ags. Subunit vaccines since the notion emergence have attracted great research interests with numerous visible and all imaginable advantages [4], including high safety without reversion to virulent state; their production needing no dangerous microorganisms; providing an alternative solution to the problematic culture for attenuating some pathogens; low risk of allergic or autoimmune reactions; customization to recognize certain pathogen-associated targets; feasible developing anticancer vaccine; carrying several peptide epitopes targeting different stages in the life cycle or subtypes of a pathogen; production in large scale in a pure state, in an economically and highly reproducible manner; high solubility

However, subunit vaccines often show a weak immune induction potency, due to lack of a large fraction of components associated with pathogen structural characteristics, which are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs) and able to activate the pattern recognition receptors (PRRs), such as the toll-like receptors (TLRs), the nucleotidebinding oligomerization domain-like receptors (NOD-like receptors), retinoic-acid-inducible gene-I-like receptors (RIG-I-like receptors), and C-type lectin receptors, to trigger as immunostimulators or an adjuvant mammalian innate immunoresponse sponsoring a series of adaptive reactions required for establishing the Ag-specific immunity [5]. Thus, while subunit vaccines are usually safer and less reactogenic than the whole organism vaccines, they often need an adjuvant or a vaccine adjuvant delivery system (VADS) to synergistically stimulate professional Ag-presenting cells (APCs) such as dendritic cells (DCs) and macrophages (MPs) for enhancing their immunization efficacy [6–10]. An adjuvant is a nonspecific immune-potentiating substance, which is capable of enhancing the body's immune

still lack vaccines and are still posing a great threat to human health and life [2].

allowing lyophilization to form stable dry products [4].

In this chapter, we describe design principles, main formulations and the state-of-the-art advances in developing novel VADSs constructed with different types of NPs, which are formed through small molecule self-assembly and herein, include liposomes, nondegradable inorganic metal NPs (mNPs), emulsions, ISCOMs. These small molecule-based NPs have been devised as a VADS with the potential to stimulate the Ag-specific humoral and cellular immune responses and are promising in preparation of next generation vaccines against a range of infectious pathogens.
